book reviews Confirming a bold prediction A look back at work to prove the semi-conservative replication of DNA.

Meselson, Stahl, and the Replication of DNA: A History of “The Most Beautiful Experiment in Biology” by Frederic Lawrence Holmes Yale University Press: 2001. 416 pp. $40 Robert Olby So much attention is given to DNA today that no small effort is required to recapture the climate of uncertainty and caution that met the launch of the double-helix model of its structure by James Watson and Francis Crick in 1953. Looking back in the light of more recent advances in molecular biology, that year seems to mark the decisive turning point. If so, why, one might wonder, did James Watson worry so much that the double- helical structure might prove to be wrong? And why did he advise his co-discoverer against accepting an invitation in 1953 to speak about their structure on the radio? Consider, too, the research of two young

CSHL ARCHIVES postdocs — Matthew Meselson and Frank Stahl — in the years 1957–58, as they worked Pairing up: Frank Stahl (left) and Matthew Meselson nailed the mechanism of DNA replication. to find evidence for the semi-conservative

form of DNA replication. Was this work Stahl with their wonderful experiment that rejoinings in the chains every five bases to CALTECH simply an elegant experiment confirming a demonstrated the semi-conservative nature overcome the unwinding problem. Holmes prediction of a model made five years before? of the replication process in the bacterium points out that even the Meselson–Stahl Granted, their experiment appears to be Escherichia coli. Published in 1958, it offered experiment seems to be disappearing from both beautiful and compelling, but did we a stunning verification of the original pre- the newest texts. Here he has recaptured really need it? Holmes, a seasoned historian diction. Meselson and Jean Weigle extended the technical and intellectual context of and professor at Yale University, leaves us the result to phage-ȕ in 1959. This was the experiment, and explained why it was not in no doubt that we did. He treats us to a followed by John Cairns’ demonstration by judged by its authors to constitute a demon- thorough analysis of the context and origin autoradiography of the molecular unity of stration of the semi-conservative replication of this famous experiment, the lives of its the phage-ȕ chromosome in 1962, which of the DNA molecule, but only, as they put it two authors during the work, the impact of clinched the case for identifying the subunits in 1958, of ‘DNA subunits’. They were clear, the published results, and finally a soliloquy as single chains. however, that they had destroyed the two on the nature and role of experiment in Reading this book should disabuse us of alternative suggestions: conservative and molecular biology. such easy impressions of life in the early days dispersive replication. The standard account is by now familiar. of molecular biology. Holmes has mined the Using the analytical ultracentrifuge at Watson and Crick’s model for DNA suggested archives, probed the scientists’ memories, Caltech run by Jerome Vinograd, and a molecular mechanism for gene replication. and absorbed the abundant literature, both their innovative caesium chloride gradient, The chains of the duplex would separate, the great and the not-so-great, and that Meselson and Stahl were able to distinguish each then providing a template upon which which in retrospect we can judge the ‘wrong’ three distinct bands representing DNA: one a complementary chain could form, thus and the ‘right’. The result is one of the most ‘light’ band from bacteria grown in a normal generating two ‘daughter’ double helices. authentic narratives in the history of molec- medium, one ‘heavy’ band from bacteria According to the model, each daughter ular biology — not a ‘winner-takes-all’ story, nourished with an isotopic ‘heavy’ nitrogen double helix carries one of the parental but a clash of differing views, a striving source, and, in between, one ‘hybrid’ band chains. The replication, as Gunter Stent put and a resolution. When the manuscript was representing DNA from the progeny of it, is ‘semi-conservative’. There was a prob- finished, Meselson read it and remarked: the latter formed under normal ‘light’ lem, though: how to unwind the entwined “It brought it all back. I can remember nutrition. These progeny DNA samples, helices in the first place. This was a formida- being in that world — it’s imperfect, but a they inferred, were composed of equal ble task but not impossible, judged Crick, time machine.” quantities of heavy and light subunits — one but to Max Delbrück it seemed insuperable. In the onward march of science, things from the parental ‘heavy’ DNA, the other Caught between the scepticism of Delbrück that are resolved are ‘black-boxed’ — stu- ‘light’ and freshly minted. The experiment and the confidence of Crick, Watson trod a dents are no longer taught how they were had thus a visual beauty to add to its other fine line, motivated by fear that the structure established — and no textbook of molecular merits: the apparently clean separation of might be wrong and hope that it would turn biology today would include a diagram of the bacterial growth on heavy and light out to be right. the ‘dispersive’ replication scheme preferred media, and the strategy of the experiment Mercifully, along came Meselson and by Delbrück, in which there are breaks and that allowed it to meet possible objections,

NATURE | VOL 417 | 9 MAY 2002 | www.nature.com © 2002 Macmillan Magazines Ltd 121 book reviews so it even swayed the reluctant Delbrück. In sex? Sperm competition This was no small achievement, to be put is crucial to understanding alongside the simplicity and substantial sexual behaviour in insects, benefit to molecular biology of caesium such as these mealworm chloride gradients for ultracentrifugation. beetles. ANDREW SYRED/SPL ANDREW Holmes suggests that the growing knowl- edge of the immense complexity of the mechanism required for DNA duplication may be starting to crowd out mention of the Meselson–Stahl experiment. When Watson and Crick suggested in 1953 that DNA replication might occur without the aid of a special enzyme, little did they foresee the complexity of the process, involving as it does not only DNA polymerase, but also the DNA helicases and primases, the proof- reading exonuclease, the sliding DNA clamp and the Okasaki fragments — a multi- enzyme system that performs its task with remarkable fidelity. Nor, perhaps, did they expect the unwinding problem to resurface again to challenge the double helix as late as the 1970s. This book joins a growing library of Philosopher’s Song to including insects, outstanding historical studies of modern include an extra competi- begging the ques- experimental biology that includes Hans- tive dimension. Ever since tions “why produce Jörg Rheinberger’s study of protein synthesis Antoni van Leeuwenhoek first looked another?” and “why in the cell-free system, Toward a History of at sperm under a microscope, and proba- just insects?” Simmons Epistemic Things (Stanford University Press, bly long before, humankind has had an argues that a comprehensive 1997) and Nicolas Rasmussen’s analysis of inkling of the wastage that occurs in male review of our current knowledge the adaptation of the electron microscope gametes. of the phenomenon in insects provides for the study of the cell, Picture Control But it was not until 1970 that a formal the broadest platform on which to base (Stanford University Press, 1999). Their theoretical framework, and some elegant any understanding of sperm competition. scholarship is impeccable and their analyses empirical support for it, emerged. Geoff To make this point he picks the field apart, perceptive and revealing, not just of an age Parker realized that when two or more paper by paper, and skilfully reassembles fast receding into the past, but of what Bruno males mated with the same female, selection it around the important conceptual issues, Latour called “science in the making”. I would favour the evolution of male traits thereby bringing sperm competition, Robert Olby is in the Department of the History that gave one sperm-owner a paternity rather than insect behavioural ecology, into and Philosophy of Science, University of advantage. This elegant and, with the benefit crisp focus. Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. of hindsight, obvious concept opened the Each chapter starts, when appropriate, floodgates to a sea of ideas and explanations. with the theoretical basis for its sub-theme, Suddenly post-copulatory guarding behav- followed by a well-structured review of the iour made sense, we began to understand empirical work. For example, the chapter the causal basis of variation in hitherto on behavioural adaptations to avoid sperm When ejaculates ignored aspects of reproductive behaviour, competition begins with a very readable and we had an elegant explanation for a distillate of the theory and modelling of collide… million million spermatozoa. mate-guarding. (Similar summaries of the Sperm Competition and its Parker’s theory had a profound effect on critical modelling and theory preface other Evolutionary Consequences in the the fledgling field of behavioural ecology — chapters and are a real bonus.) The chapter Insects he laid a cornerstone that defined it and then reviews the substantial literature on by Leigh W. Simmons illustrated the value of combining model- mate-guarding and alternative hypotheses Princeton University Press: 2001. 434 pp. ling, empiricism and a productive disregard for this behaviour, before moving on to the £24.95 (pbk) for disciplinary boundaries to address ques- more contentious subject of male mate Michael T. Siva-Jothy tions about the how and why of evolution. choice. By leaving the open-ended subjects Parker used insects as his model system: they until the end of their chapters, Simmons A million million spermatozoa were particularly susceptible to this form contextualizes the new areas and so guides All of them alive of selection and were amenable to the the reader to paths that have potential for Out of their cataclysm but one poor Noah combined physiological, anatomical and future work. Dare hope to survive. behavioural studies that revealed the nature This book is an excellent summary of And among that billion minus one of the adaptations that resulted. a recent, important and relatively large Might have chanced to be Having served his intellectual apprentice- addition to our understanding of evolution Shakespeare, another Newton, a new Donne ship in Parker’s laboratory and played a and its consequences. It is an essential read — significant part in directing the field, Leigh for anyone interested in the reproductive But that One was Me. Simmons is better qualified than most to determinants of fitness. I define the current state of sperm competition. Michael T. Siva-Jothy is in the Department of If Aldous Huxley had lived another seven However, there are already three books that Animal and Plant Science, University of Sheffield, years he might have amended his Fifth examine sperm competition in a range oftaxa, Sheffield S10 2TN, UK.

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